The major emphasis of our research on the prevention of physical frailty and loss of independence has been on the adaptations to exercise. However, because most Americans are not motivated to exercise, we have started to evaluate other approaches to maintenance of health and prevention of frailty. Of these, the most powerful appears to be DHEA replacement therapy. In this context, the overall goals of this study are to determine whether long term dehydroepiandrosterone (DHEA) replacement therapyhas beneficial effectsthat could (a) delay the development of frailty and disability, (b) protect against development of type 2 diabetes and coronary artery disease, (c) improve quality of life, and d) obtain information on the mechanisms of DHEAaction. DHEAand DHEA sulfate (DHEAS) plasma concentrations peak at -20 yr of age and decline rapidly and markedly after age 25 yr. DHEAis a PPARa activator. PPARa plays major roles in regulating lipid metabolism and controlling inflammation. DHEA also appears to have anabolic effects on muscle and bone. The study proposed here is a randomized, double blind, placebo-controlled trial of DHEA replacement. It is designed to determine the effects of 12 mo of DHEA replacement in 65-75 yr old women and men on (a) truncal and visceral fat, (b) insulin resistance and serum triglycerides, (c) muscle mass and strength, (d) bone mineral density, (e) chronic inflammation, (f) arterial-endothelium-dependent vasodilation, and (g) sense of well being. The specific aims of this study are to test the hypotheses that 12 mo of DHEA replacement will (a) Result in significant decreases in truncal and visceral fat by shifting metabolism to fat oxidation and increasing energy wastage; (b) Decrease insulin resistance and decrease serum triglycerides; (c) Increase muscle mass and strength, by decreasing catabolic stimuli and increasing anabolic stimuli; (d) Increase bone mineral density by increasing anabolic stimuli and decreasing catabolic stimuli; (e) Reduce chronic inflammation and decrease pro-inflammatory cytokine production by peripheral blood mononuclear cells; (f) Improve arterial endothelium dependent vasodilation; and (g) improve general sense of well being. A major emphasis of this research is on the mechanisms responsible for the biological effectsof DHEAreplacement.